About 30% of AIDS patients suffer from HIV-associated dementia (HAD). Whether neurotropic or neurovirulent HIV-1 variants are involved in HAD is not known. In the current grant period we described HIV-1 R5 envelopes from brain tissue of individuals with neuropathology that are highly fusogenic and tropic for macrophages. These envelopes exploit low amounts of CD4 and CCR5 for infection and may confer a broader tropism for T-cells as well as macrophages. Such envelopes may represent neurotropic or neurovirulent variants. Our hypothesis is that highly macrophage-tropic HIV-1 variants replicating in brain tissue are associated with neurotropism, neurovirulence and increased viral fitness. The brain may also act as a sanctuary site where persistent replication of highly macrophage-tropic viruses during HAART results in the evolution of drug resistant variants. If highly macrophage-tropic variants have increased fitness for CD4+ T-cells, they may then recolonize immune tissue, contributing to CD4+ T-cell depletion and disseminating drug resistance mutations. Here, we propose four aims that will to investigate whether highly macrophage-tropic envelopes are (1) limited to individuals with neuropathology, (2) present at different sites inside and outside the brain and (3) associated with drug resistance mutations in brain tissue of HAART treated patients. We will also evaluate whether highly macrophage-tropic brain envelopes confer increased fitness for CD4+ T-cells and thus carry the potential to re-colonize immune tissue. This application fits well with PA-04-154, which particularly requested applications proposing to study "molecular diversity (of HIV) and functional consequences" as well as "emergence of drug resistance in CMS". The proposed experiments will greatly extend our knowledge of highly macrophage-tropic variants in brain and other tissues, as well as providing important insights into their neurotropism and their association with neuropathogenesis and drug resistance. Results obtained may lead to the design of novel strategies to treat or prevent HIV dementia.